Structural and Biochemical Studies of Dihydrofolate Reductase from Streptococcus pyogenes as a Target for Antifolate Antibiotics

Streptococcus pyogenes, a beta-hemolytic bacterium, causes a wide spectrum of infections in human including pharyngitis, tonsillitis, scarlet fever, rheumatic fever, and necrotizing fasciitis. Streptococcal infections can also exist as co-infection with methicillin resistant Staphylococcus aureus (MRSA). Trimethoprim-sulfamethoxazole (TMP-SMX) combination has been used for treatment of S. pyogenes and MRSA co-infection. However, resistance to TMP, an inhibitor of dihydrofolate reductase enzyme (DHFR), has challenged the efficacy of TMP-SMX combination. We explored the activity of a series of novel DHFR inhibitors against S. pyogenes. This study identified potent inhibitors of DHFR enzyme from S. pyogenes with excellent inhibitory activity against the growth of the live bacteria. We determined, for the first time, the crystal structure of S. pyogenes DHFR which provides structural insights into design and development of antifolate agents against this global pathogen.